It is proposed to initiate a rationally designed program to study the generation, chemistry, and potential synthesis applications of quinone methides, and semiquinone methides. Quinone methides are extremely reactive intermediates that have seen only limited use in carbon-carbon bond forming reactions. The potential biological importance of semiquinone methides has only recently been proposed and very little is known about the chemistry of these types of compounds. The studies proposed should lead to powerful new methodology for the synthesis of compounds with oxidized aromatic rings, as well as better define the importance and exact electronic nature (quinone methide vs. semiquinone methide) of these types of compounds in biological processes. The specific aims for the proposed project include: generalization of existing methods, and development of new methods, for the preparation of quinone methides; exploration of the use of quinone methides as cyclization initiators (these extremely reactive intermediates might be generated under mild conditions making them ideal as cyclization initators for olefin cyclizations); exploration of the transition state topology for quinone methide initiated cyclizations; demonstration of the general utility of quinone methides in total synthesis with a biomimetic synthesis of minus or plus-futemone via the proposed biosynthetic intermediate, a quinone methide, and a synthesis which utilizes a semiquinone methide as an intermediate; development of a general method for the synthesis of semiquinone methides; exploration of the reaction of semiquinone methides with nucleophiles; investigation as to whether semiquinone methides will react as carbon centered radicals in the formation of new carbon-carbon bonds. The ultimate health significance of the chemistry proposed here rests with the potentially powerful new synthesis methods to be developed, and the insights to be gained into the chemistry of quinone methides and semiquinone methides which may serve as mimics of structural moieties present in more complex biological systems. Quinone methides and semiquinone methides have both been proposed to be important intermediates in biosynthesis, as well as being the active forms of several anticancer drugs. Insights into their chemistry could have broad implications in understanding a number of important biological processes and serve as the basis for the design of new more potent anticancer drugs.